Candida albicans is extremely well adapted to life in its mammalian host, able to harmlessly co-exist in multiple host niches while retaining the capacity to cause debilitating mucosal or life-threatening systemic infections. Over 50% of healthy patients carry Candida in their mouths while oropharyngeal candidiasis occurs in upwards of 90% of HIV+ individuals progressing to AIDS. Until recently, the organism was thought to be asexual, but a highly specialized mating cycle has now been uncovered. While studies have begun to elucidate the mechanism of sexual reproduction in C. albicans, the role that sex plays during commensalism and infection has not been addressed. This proposal will focus on two unique adaptations to the sexual reproductive cycle of C. albicans that have been uncovered in the Bennett lab. The first is the potential for strains to undergo autocrine pheromone signaling and same-sex mating. Same-sex mating has been shown to occur in other pathogenic fungi and may be favored in pathogens where encounters with potential mating partners of the opposite sex are rare. Pheromone signaling also influences cell-cell cohesion and biofilm formation by C. albicans. The present proposal will therefore test if autocrine signaling leads to increased biofilm formation either on silicon elastomer or dental acrylic surfaces. In addition, the experiments proposed will determine the spatial and temporal regulation of pheromone signaling within a mammalian host. Experiments outlined in the second Aim will be the first to characterize the recombinant products formed by the parasexual mating cycle of C. albicans. Completion of the studies proposed here will determine if parasexual progeny include isolates that have altered virulence attributes. It is worth noting that many of the parasexual isolates are aneuploid, carrying three copies of some chromosomes, a feature that has been associated with increased drug resistance in clinical strains. It will therefore be revealing to test our collection of parasexual strains for their resistance to antifungal drugs. Given the prevalence of drug resistance in the clinic, it is expected that these studies will be important in determining which aneuploidies cause drug resistance, and will provide new insights into how resistant strains are formed in the wild. Completion of the experiments proposed in the second Aim will also shed light on the influence of environment on the attributes of parasexual progeny strains. These studies are relevant as they are the first to look at the role of the sexual cycle in C. albicans and how it affects commensal growth and pathogenesis.